Recent technical advances have made pancreatic islet cell transplantation a feasible approach to the treatment of insulin- dependent diabetes mellitus (IDDM). However, the need for continuous, often debilitating, immunosuppressive drug therapy in transplant recipients makes the use of this therapy in diabetic patients most problematic. Thus, the development of long term donor-specific tolerance remains a primary goal of transplant biology. Activation of graft-specific pathogenic T-lymphocytes requires a first signal originating from the ligation of the TCR complex and an additional second co-stimulatory signal. However, novel immunotherapies successfully developed in small animal models to block costimulation often fail to induce the desired immunologic effects in large animals. It is critical to move these therapies forward towards the clinic using primate models that lack the confounding factors present in clinical transplantation. In order to accomplish this goal, the following specific aims are proposed. Specific Aim number 1. To determine the effect of blockade of the CD28/B7 co-stimulatory pathway on the survival of allogeneic islet cells transplanted into insulin- dependent Cynomolgus monkeys. In this study, we propose to administer CD28/B7 antagonists short-term in the absence of other immunosuppressive drugs, to prolong pancreatic islet allograft survival, prevent the development of donor specific antibodies and promote tolerance in a non-human primate model of islet transplantation; Specific Aim number 2. To integrate costimulation inhibition into novel drug combination treatment strategies in the non-human primate in order to establish consistent long term donor-specific tolerance. Antagonism of CD28 co-stimulation, even utilizing optimal reagents and dosing, may not completely inhibit T cell activation and differentiation. We hypothesize that additional treatments (anti-IL-2R, anti-ICAM- 1, 4-1BBFc) aimed at preventing the development of proinflammatory cell-mediated anti-donor responses will facilitate engraftment and induce a consistent donor specific tolerance in a non-human primate transplant model. Together the experiments proposed above will provide a detailed study of co- stimulation blockade in an islet transplant model in non-human primates. The immunologic, biologic and physiologic studies will afford us an opportunity to explore the basis of T cell activation and tolerance induction. The outcome of these studies will have important implications for islet cell transplantation for the treatment of IDDM.